Psychosis is one of the most dreaded disease of the 20th century and spreading further with continuance and increasing incidences in 21st century. Psychosis means abnormal condition of the mind. People suffering from psychosis are said to be psychotic. A wide variety of central nervous system diseases, from both external toxins, and from internal physiologic illness, can produce symptoms of psychosis. It is considered as an adversary of modernization and advanced pattern of socio-cultured life dominated by western medicine. Multidisciplinary scientific investigations are making best efforts to combat this disease, but the sure-shot perfect cure is yet to be brought in to world of medicine.
Natural antipsychotic agents are an important area of the current research and are in good demand all over the world because they are better than synthetic drugs as they do not possess serious side effects and chronic toxicity. To the best of our knowledge there are many antipsychotic drugs but all are synthetic, so there is need to search for the potential antipsychotic drug from the plants.
Indole alkaloids are aromatic hetrocyclic organic compounds and occur in a large number of plant families. Many reviews have dealt with their distribution, structure, properties and biosynthesis. The indole structure can be found in many organic compounds like amino acid tryptophan and in tryptophan containing protein, in alkaloids and in pigments. They have been reported to possess various biological activities such as antitumor, antimicrobial, antihypertensive (Verpoorte, R. In Alkaloids: Biochemistry, Ecology and Medicinal Applications; Roberts, M. F. & Wink, M., (Eds.); Plenum Press; New York, 1998, pp 397-433), antileishmanial activity, antibacterial activity.
The genus Rauwolfia belongs to the family Apocynaceae and five species of this genus are native to India. R. tetraphylla L. syn. R. canescens L. (Compend. Indian Med. Plants, Vol. 1, Rastogi&Mehrotra, PID, New Delhi, 1990, p. 340) is an economically important plant, which is cultivated on commercial scale in India. The plant is important because of the presence of nearly 30 alkaloids in its roots: ajmalicine, reserpine, sapagine, deserpidine, rescinnamine, serpentine, ajmalidine, alloyohimbine, chandrine, corynathine, iscajmaline, neo ajmaline, papaverine, raunatine, raunoline, rauwolscine or (α-yohimbine), reserpiline, reserpinine, reserpoxidine, serpinine, serpentinine, thambine, ajmaline and yohimbine [(Farooqi and Sreeramu, 2001, Cultivation of Medicinal and Aromatic Crops. University Press Ltd., India, pp: 210-211), J. Amer. Chem. Soc. 79(5):1217-1222].
From the leaves of R. tetraphylla N(α)-demethylaccidine, tetraphylline, tetraphyllicine [(Phytochemistry, 28(3): 1989, 961-962), J. Amer. Chem. Soc. 79(5): 1217-1222], aricine, isoreserpiline, tetrahydroalstonine, a yohimbine isomer (Rev. Cubana Farm. 1982, 16, 28; Chem. Abstr. 1982, 97, 107095 q; Rev. Cubana Farm. 1982, 16, 316; Chem. Abstr. 1983, 98, 176193 c); α-yohimbine and reserpiline have been isolated (Rev. Cubana Farm. 1982, 16, 251; Chem. Abstr. 1983, 98, 157873 h), (Compendium of Indian Medicinal Plants: Vol. 3 1980-1984 by Ram P. Rastogi, B. N. Mehrotra).
Yohimbine has been used to facilitate recall of traumatic memories in the treatment of posttraumatic stress disorder (PTSD). Yohimbine is used in arteriosclerosis and angina pectoris, and has been used as a local anesthetic and mydriatic and for its purported aphrodisiac properties (http://www.lookchem.com/YOHIMBINE/). According to one study, oral yohimbine supplementation may actuate significant fat loss in athletes (Ostojic S M, Res Sports Med. 2006, 14 (4): 289-99). In veterinary medicine, yohimbine is used to reverse anesthesia from the drug xylazine in small and large animals. Yohimbine hydrochloride is a selective competitive alpha-2 adrenergic receptor antagonist. The alpha-2 receptor is responsible for sensing adrenaline and noradrenaline and telling the body to decrease its production. Yohimbine also antagonizes several serotonin receptor subtypes: 1 A (inhibitory, behavioral control), 1B (inhibitory, vasoconstriction), 1D (inhibitory, vasoconstriction), and 2B (smooth muscle contraction). Since yohimbine is an antagonist, it will decrease the effects of these receptors, thus causing excitation, vasodilation, and smooth muscle relaxation. In addition to all these pharmacological activities, yohimbine creates numerous side effects such as rapid heart rate, high blood pressure, over stimulation, insomnia. Some effects in rare cases were panic attacks, headaches, dizziness and skin flushing. More serious adverse effects may include seizures and renal failure. Yohimbine should not be consumed by anyone with liver, kidney, heart disease or a psychological disorder.
On the other hand, α-yohimbine(17α-hydroxy-20α-yohimban-16β-carboxylic acid methyl ester) or rauwolscine is one of the isomer of yohimbine (17α-hydroxy-20β-yohimban-16α-carboxylic acid methyl ester) and does not possess side effects. It is one of the constituent of R. tetraphylla leaves and has shown quite different pharmacological activities to those of yohimbine such as standard □2-adrenergic antagonist, partial agonist at 5-HT1A receptors. (Arthur et al, 1993, Biochem. Pharmacol. 45: 2337, Hieble et al 1995, J. Med. Chem. 38, 3415, Uhlen et al, 1998, Eur. J. Pharmacol. 343: 93). α-yohimbine was more potent than RX 781094 in blocking these alpha-2 adrenoceptorsin-vivo where as both compounds were equipotent at alpha-1 adrenoceptors. α-Yohimbine was found about 25 times more selective than RX 781094 and 2 times more alpha-2 adrenoceptors selective than RS 21361. RX 781094 was approximately 3 times more effective than α-yohimbine in antagonizing the centrally mediated alpha-2 adrenoceptor-induced hypotension and sedation of clonidine in rats and mice (Timmermans et al, J Pharmacol Exp Ther., 228, (3), 1984, 739-48). Alpha 2-adrenergic receptor antagonist α-yohimbine may function as an agonist at the serotonin 1A (5-HT1A) receptor expressed in human brain. α-Yohimbine and yohimbine are partial agonists for the human 5-HT1A receptor (Biochempharmacol 1993, 45, (11) 2337-41). α-Yohimbine, an alkaloid of R. canescens Linn. (Chatterjee et al Ind. Chem. Soc., 18, (33), 485, 1941) was found to be a potent adrenolytic compound (Chakravarti, Science and Culture, 8, (8), 1942). Rauwolscine behaves as competitive antagonist and displays greater efficacy in relaxing basal tension. (Biochemical pharmacology 66, 2003, 927-937).
Reserpiline is markedly sympatholytic and hypotensive with no noticeable depressant effects on the central nervous system and sedative properties. In comparison with reserpine and rescinnamine it does not induce appearance of gastric ulcers, has no laxative effect and lacks other side effects (African ethnobotany: poisons and drugs: chemistry, pharmacology, toxicology By Hans Dieter Neuwingerpg 133, 1996, chapman & Hall GmbH, Weinheim, Germany). Isoreserpiline and reserpiline have antidiabetic activity (Traditional medicine for modern times, antidiabetic plants. Eds. AmalaSoumyanathpg-56, 2006, CRC Press, Taylor & Francis, Boca Raton Fla., USA).
Alastonine an alkaloid from the genus Alastonia possesses antimalarial activity, but is more toxic than quinine as shown in ducklings, mice and rats. (Wakim and Chon, J. Pharmacol. Exptl. Therapeutics 90 (1), 57-67, 1947). The indole alkaloid alastonine has been identified as the major component of a plant-based remedy, used in Nigeria to treat mental illness by traditional psychiatrists. It possesses clear anxiolytic activity, mediated by 5-HT2A/2C serotonin receptors (Elisabetsky and costa-campose CAM 2006; 3(1) 39-48 doi: 10.1093/ecam/nek011). Alastonine is the major component of plants used by Nigerian psychiatrists as anti-dementia drugs. Recent researches have shown that alastonine increases seratonergic transmission and intraneuronal dopamine catabolism. (Linck et al, eCAM 2009; page 1-7 doi:10.1093/ecam/nep002). Experimental data have shown that unlike clozapine, alastonine does not possess pro-convulsant activity and deserves to be scrutinized as a model for the development of newer antipsychotics. (costa-campos et al J. Ethnopharmacol 93: 307-310, 2004).
To the best of our knowledge there is no report for the antipsychotic activity in the leaf extract of R. tetraphylla and in the compounds isolated from the leaf extracts of R. tetraphylla: α-yohimbine, reserpiline and a mixture of 10-demethoxyreserpiline and 11-demethoxyreserpiline in 1:1.5 ratios. Hence we wish to report the antipsychotic activities in the leaf extracts of R. tetraphylla and in α-yohimbine, reserpiline and a mixture of 10-demethoxyreserpiline and 11-demethoxyreserpiline in 1:1.5 ratios against dopaminergic-D2, and serotonergic (5HT2A) receptors (in vitro) and amphetamine induced hyperactive mouse model (in vivo). Isolation of α-yohimbine, reserpiline and a mixture of 10-demethoxyreserpiline and 11-demethoxyreserpiline in 1:1.5 ratios were carried out from the leaves of R. tetraphylla. 
Earlier the major thrust of antipsychotic drugs development was centered around the dopamine since all antipsychotic drugs potently block dopamine receptors, but in the recent past more attention has been focused on serotonin 5-HT2A and 5-HT receptors as atypical antipsychotic drugs (e.g. clozapine, olanzepine, and risperidone) potently block these receptors.
It has been common observation that herbal formulations are better than the synthetic drugs as they do not possess serious side effects and chronic toxicity. So in order to find out more potent antipsychotic plant product or herbal formulation, we carried out a systematic bioactivity guided fractionation and isolation of antipsychotic compounds from the leaves of an Indian medicinal plant R. tetraphylla. The subject mentioned below specially describes the manner in which the antipsychotic extracts and compounds were obtained.